RESUMEN
A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/síntesis química , Broncodilatadores/síntesis química , Antagonistas Muscarínicos/síntesis química , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Triazoles/síntesis química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Animales , Disponibilidad Biológica , Broncoconstricción/efectos de los fármacos , Broncodilatadores/farmacocinética , Broncodilatadores/farmacología , Células CHO , Cricetulus , Perros , Humanos , Ipratropio/farmacología , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacología , Ratas , Receptor Muscarínico M3/antagonistas & inhibidores , Xinafoato de Salmeterol/farmacología , Bromuro de Tiotropio/farmacología , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
A highly selective method to protect the 11 beta-OH position of steroid (1) has been developed. This is achieved via double silyl protection of the 11 beta, 17 alpha-diol, followed by selective desilylation of the 17 alpha-OH under basic conditions without the need for a fluoride source.
Asunto(s)
Esteroides/química , Esteroides/síntesis química , Relación Estructura-ActividadRESUMEN
The administration of compounds by a dry-powder inhaler presents significant challenges to the development and discovery chemist, owing to the stringent requirements placed upon the physical characteristics of the active pharmaceutical ingredient and the high complexity of the molecules concerned. The current state of synthetic chemistry technology is such that commercial syntheses of these compounds are demanding but achievable. While synthetic chemistry will remain a major component of the development of inhaled therapies, the main challenge facing practitioners in this area is the early identification of a suitable solid form. Further advances in the prediction of solid-form properties would significantly enable this field and may allow triage of molecules to be carried out at the design stage of projects.